EXPRESSION OF HUMAN HEPATIC GLUCOKINASE IN TRANSGENIC MICE LIVER RESULTS IN DECREASED GLUCOSE-LEVELS AND REDUCED BODY-WEIGHT

Glucokinase is the predominant hexokinase in pancreatic beta-cells and liver parenchymal cells and functions as a critical component of the glucose-sensing apparatus in these glucose-responsive cell types, In t he beta-cells, the sensing leads to insulin secretion, while the role in hepatocytes is thought to be in hepatic glucose uptake, To determin e the physiological response to an increase in hepatic glucokinase exp ression, transgenic mice expressing the human hepatic glucokinase gene under the control of a liver-specific human apolipoprotein AI gene en hancer were generated, Transgenic mice had twofold higher total fastin g hepatic glucokinase mRNA, which resulted in a modest 20% increase in fasting glucokinase activity, These animals showed lower fasting plas ma glucose, insulin, and lactate levels and improved tolerance to gluc ose, In addition, glucokinase transgenic animals weighed less and had lower BMI than nontransgenic animals, Thus, glucokinase transgenic ani mals demonstrate that a modest change in hepatic glucokinase activity enhances the metabolism of glucose.